title: Origin and function of myofibroblasts in kidney fibrosis.
abstract: Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Taduri
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Connell
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Teng
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.forename: Craig
authors.initials: C
authors.lastname: Woda
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology*; D020286:Pericytes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000199:Actins; D000941:Antigens; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D020797:Receptor, Platelet-Derived Growth Factor beta; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D000099216:Chondroitin Sulfate Proteoglycan 4; C544013:alpha-smooth muscle actin, mouse